1. Field of the Invention
This invention relates to the inhibition of parasitic protozoa of the genus Plasmodium with camptothecin compounds. Camptothecin compounds have the general ring structure shown below. ##STR1##
The invention also relates to the treatment of animals having plasmodia infections with camptothecin compounds.
2. Background of the Invention
Sporozoan protozoa of the genus Plasmodium are vertebrate parasites that infect primarily liver and red blood cells and may give rise to malaria. There are at least four species of plasmodia that normally infect humans, i.e., P. vivax, P. ovale, P. malariae and P. falciparum. Three additional species P. cynomolgi, P. knowlesi and P. brasilianum infect non-human primates.
Plasmodia infection is initiated by the bite of an infected insect, generally the female Anopheles mosquito, which injects infective sporozoites into the mammalian host. In the first stage of development, parenchyma cells of the liver are infected within which develop infective merozoites. Rupture of infected liver cells releases the merozoites into the blood stream where they infect circulating erythrocytes (red blood cells).
The parasites in the red blood cells multiply by ethrocytic schizogony dividing into erythrocytic merozoites. The host cell ruptures and merozoites are released into the bloodstream. The released parasites invade new red blood cells producing the symptoms of clinical malaria.
The periodic symptoms of malaria are related to the blood stream life cycle events of the plasmodia organisms. An initial chill begins as a generation of parasites rupture their host red cells and enter the blood stream. Nausea, vomiting and headache accompany this phase. A febrile stage follows the chill and is characterized by a spiking fever. During the febrile stage, parasites presumably enter new red blood cells. A sweating stage follows as the fever subsides.
Current therapy for plasmodia infection is treatment with one or more of the compounds quinine, chloroquine, amodiaquin, quinocide, primaquine, quinacrine, chloroguanide, pyrimethamine, trimethoprim, mefloquine, artemisinin, doxycycline, sulfadoxine and halofantrine. The large scale use of these drugs has resulted in the emergence of drug-resistant strains of plasmodia. During the 1960's, large scale use of chloroquine resulted in the emergence of chloroquine-resistance strains, for example. For chloroquine-resistant plasmodia infections, combinations of drugs are administered, for example a combination of pyrimethamine with sulfadoxin or quinine with sulphametopyrazine.
In view of the emergence of resistant plasmodia strains to existing drugs, a need continues to exist for new drugs that are toxic to plasmodia and/or suppress plasmodia infections.